Missing Link FOUND! Reverse Immune Decline and Inflammaging | Dr. Anurag Singh

The more CD8T cells you have, the better your longevity. Health predictor. This is the number one intervention that has been shown to sort of reverse a lot of these immune aging decline. Mitopure is your cellular health glue or your lubricant. Biologists have described nine biological hallmarks of aging. If I were to redraw these hallmarks, I would put one in the middle, and that will be.

You're listening to the Human Upgrade with Dave Asprey. Today we're going to talk about mitochondria. Good God. How many times am I going to talk about mitochondria on the show? An infinite number of times. One for each number of mitochondria in your body. Okay, not really, but I've become increasingly convinced over the last, oh, 25 years of studying my mitochondria and mitochondria in general that they are at the foundation of our interface with reality and that they control a lot more in our bodies than. Than we're aware of. And that science, every single day is figuring more and more out, like, oh, let's study the brain. Oh, let's study neurons or glial cells. Oh, look, there's mitochondria behind them. Let's study athletic performance. Oh, look, mitochondria. Sex hormones, mitochondria. So this is why you keep hearing about them on the Human Upgrade. It's because they matter and because all the different tools you can use will make you live longer and make you perform better at whatever it is you want to do as a human being. And on that note, we're going to talk about some things with mitochondria in your skin today and your immune system. And we're going to talk about a compound called urolithin A that you may have heard about on the show today. Our guest is Dr. Anurag Singh, who's chief medical officer at Timeline Nutrition, and he's a top mitochondrial and cellular health expert and has an MD in internal medicine with a PhD in immunology, has led 50 clinical trials and written 40 plus scientific articles and has 15 patents. In other words, this is a guy who is steeped in mitochondria because they kind of run everything in your immune system. And is that actually true? Do mitochondria really run everything in your immune system or am I being hyperbolic?

Well, mitochondria, Dave, are in every cell type except your red blood cells. So they are, of course, in greater abundance in metabolic cells like our muscle cells and brain cells and heart cells, but they're very Very important to what I call immune fatigue with aging. So as with aging, you know, our immune system declines, and principally now the science is showing that the key driving factor is mitochondrial dysfunction.

I've done a lot of work on reversing aging in the cells. I recently did another thing to change the central aging clock in my brain. Did a whole podcast on that and using stem cells and focused ultrasound. But the one area that I'm most concerned about from aging is immune system aging. To address that, years ago, I did cultured natural killer cells. I took mine out, amplified them, and put them back in, which could find to really do this at a heavy level. But it turns out there's some things we might be able to do to lessen the effect of the immune system on aging. In my case, because I had chronic fatigue, I've had autoimmune issues probably for my entire life. This is one of my big risk factors. Yeah, what do we know about inflammaging? What is it? And what do mitochondria have to do with it?

Yeah. So I've spent 20 years studying mitochondria, and even a greater time studying the immune system. And. And funny enough, the two roads are now converging Chronic inflammation and sort of these leaky cells. So, you know, the more as we age, these cells become what they're calling zombie cell or senescent cells or leaky cells. They start releasing these fragments of cellular debris, and that causes sort of a chronic inflammation, you know, and as we age, this inflammation rises. And that's the term we have called inflammaging. And that's a broader part of what I call the three hallmarks of immune aging. One is inflammaging, as I just described. It's like this increasing chronic inflammation with aging. The second is immunosenescence. So you started with a very technical term, NK cells, natural killer cells. So with aging, we lose our lymphocytes. So our body shifts from these trillions of immune cells, where we have more lymphocytes, which are what I call the third arm of the elite, our immune system. They decline with aging, and that's immune senescence. And third is really, you know, this concept of immune resilience. And that's where we can talk about mitochondrial health and how that is key for boosting your immune system.

If we look at all of the different causes of aging, and my book Superhuman on longevity, I identified about 7. Some people identify up to 12. How important is immune aging compared to all the other things that happen?

Yep. So, you know, these are whether. Seven biologists have described nine biological hallmarks of aging, and now we've actually expanded that universe and included three more. And these three are actually, I think these are the foundational pillars of what causes these other things. And these three are chronic inflammation, gut dysbiosis, and a loss of what they call macroautophagy, which is basically, you know, mitophagy and lysophagy, things that allow you to clean yourself. So I think if I were to draw redraw these hallmarks, I would put one in the middle and that will be inflammaging and chronic inflammation. And they all can converge on this one because I think poor nutrient sensing or epigenetic modifications or mitochondrial dysfunction, you can explain all of them with this concept of inflammation. And that's what biology and scientists and clinical clinicians are finding.

Now, if your immune system is working perfectly, you would have very little inflammation except from exercise or something like that.

Right.

What percentage of people have immune systems that work in, you know, that work really well these days? It seems like it's almost impossible.

Yeah, I mean, listen, the more sedentary we are, the more processed food we eat, the more artificial dyes that we are getting in our processed foods, you know, things like this. And then all the chronic exposure of stress, sleep, all these are causing inflammation in a background. And there is a very thin line between good and bad inflammation. A little inflammation is good. As you mentioned, exercise causes a little low grade inflammation. That is good. But over time, with all the cellular systems not working in perfect harmony, this leads to really an accumulation of inflammation and the body can't control it. And so what I see, actually we've looked at a lot of. And if, look at all these longevity studies and blue zones, et cetera, you'll find that they have very low grade C reactive protein or interleukin 6. These are factors that are in our blood that are made by immune cells. And these are signs of if you have good inflammation or not. And so the more C reactive protein you have, the more cardiovascular diseases you have, the more brain degeneration you have. So you can actually link just by one marker or two, mark, the entire sort of longevity landscape.

So if we wanted to measure the number one thing, it would be C reactive protein.

I think that's the old school. So I trained in that medical school where they said inflammation is crp. Right. That's probably the one tool. And the second, maybe you can do what is called as a total leukocyte Count. So you can count the number of your lymphocytes and, and your, your neutrophils and all these other cell types. These were the two things that probably even till today the clinicians are using. Now science is progressing at such a high speed that with little drop of blood we can look at more than just CRP. So interleukin, all these interleukins like interleukin 1 beta, TNF alpha, these are all factors. When the cells get stressed, the immune cells, they, they, they release a lot of these factors. And so you can measure with a tiny drop of blood a and then with a little drop of blood I can actually look at millions and millions of cells in the blood which will give you like an atlas of your immune system. Now this technology sounds a bit Star Trekkie, but it's coming in, let's say the clinicians will know more about it and start using it in the next five years, ten years time frame.

And this is different than like DNA methylation, true age kind of things or is it related?

So true. Yeah, true diagnostic or looking at epigenetic age. You're just looking at methylation patterns inside immune cel, any other kind of cells. Here you're using a technique called as flow cytometry. So you take let's say one ML of blood that you take, go for your regular blood checkup. There are about 5 to 10 million immune cells. So you take these and you run them on a very high throughput machine called a flow side emitter and you can using dyes, recognize every part of your immune system. So you know your first line of defense. These are what I call the police forces. These are things like neutrophils and other cells that help in wound. Then the second line of defense is your antibody producing and the third is really what you are calling these T cells and NK cells that are these like I call the elite forces of the immune system. And so using this panel we can tell who has low immune cells, T cells, low NK cells, who has more of. Yeah, and I think this is known to correlate the more CD8 T cells you have, the better your longevity health predictor.

So how do I have more of the CD8 cells?

So even in the CD8 T cells you have two kinds. One are what we call the memory T cells. That's where vaccines are given. So you give a vaccine which is like attenuated part of a virus or whatever and these cells remember so the next time they see a virus or, or a cancer part Of a cancer cell, they attack it. But these viruses or cancer cells are very smart. They fatigue these immune cells. And so you get basically a lot of bad goodies in your body over time and over aging. And so what you really need is these naive stem cell, like CD8T cells. And most of us can make it because we have an organ here called the thymus that after a 20, starts going, you know, involuting and becomes smaller and smaller. So we can make. And that's the term t cell comes from, because they all educated in the thymus. So if there are strategies to boost these knife CD8T cells, then we can reverse partially in aging.

One of the things that happens as we age is our thymus goes away. Why does it go away?

It's funny you say that. I think it's like a programmed. If you talk to folks like Dave sinclair, They'll tell you these are, you know, the whole immune system is like a compact disc. It's all written. And the thymus has a certain, what we call in the immunology field, sequence of patterns that it can recognize. A pattern of viruses, pattern of cancer cells. And once around in our. It peaks in our mid teenage and twenties. It feels like it's done enough. It automatically starts receding. And there is a lot of effort being put in this field to keep the thymus around long time. So there are hormones that, you know, people can give thymus then or other. There's even efforts to reconstitute the thymus to regrow the immune system. So there are these strategies out there. But why exactly it involutes? I think it's just programmed in our aging. And I don't think there's a clear answer why it involutes. Today.

I've looked at protocols that regrow the thymus that seem to make people much younger. And these are complex things with growth hormone and metformin and things like that.

Yep.

Those are relatively extreme. And there's risks from taking growth hormone.

Yep.

What are some things we could do to help with this inflammation that are a little bit more affordable and accessible?

So fasting, believe it or not, this is the number one intervention that has been shown to sort of reverse a lot of these immune aging decline. There have been studies done by Walter lungo and colleagues that show that not only do you reverse this biological age that you were talking about, this methylation pattern, but you actually induce deep immune changes. So these CD8T cells come back. And we have been, you know, I'm a trained immunologist and all the data we've been seeing with certain nutritional interventions, and we can talk about one of them, called urolithin A, or gut metabolites, points to a deep connection between our gut and our immune system. A lot of immune cells are actually in our gut. They are educated also in the gut. And so what we are seeing now is that a lot of these mitochondrial boosters can be used to rewire and rejuvenate the immune system and get more of these NK cells, get more of these CD8 T cells.

One of the things that you're most known for is urolithin A, the things you're doing with timeline. And for listeners, if this is the first time you've heard me interview Anurag, I've been using timeline since it first came on the market because there's 10 years of really profound research in this. This postbiotic, technically, is what you could call it, for doing all sorts of good things for mitochondria, including dealing with inflammating. So what is the role of urolithin A in, with or without fasting, in affecting the CD8 cells or the thymus or just inflammaging?

Yeah. So I think about a year and a half back, there was a very fascinating podcast you had with a collaborator of mine, actually, who was an oncologist, Dr. Dominique Denk, and he's a very young clinician. He has been studying the immune system for a long time, and he's been studying cancer and cancer models, especially colorectal cancer, and models like. And what they started seeing in cancer patients and in these colorectal cancer models was that the immune cells had depleted mitochondria. These sort of these elite force equilibrium. These are stem cell, like CD8T cells and K cells, et cetera. And they started looking for interventions that could boost mitochondria inside these T cells in these models. And what they found, actually, that in both these models and in a dish where they took out human cells and they cultured them, with this postbiotic urolithin A, they could boost the more the abundance and the quality of the mitochondria. And so when he showed me that data, and I think he came on your podcast about a year and a half back, we said, hey, you know, we have to, you know, we have to run a randomized clinical trial in healthy folks to see if, you know, from our furry animals, whatever you're seeing in these models can be translated into humans. And at the time I was running trials with urolitin A in healthy folks, more on the muscle side. But we will always look at blood biomarkers and CRP as we started talking about C reactive protein would always be dampened, whether it was older adults or a bit overweight middle aged adults. So we did this trial, we ran this with the Buck Institute of Aging, which is one of the top research institutes where they have this technology to really do a deep immune phenotyping. And after a month of taking urolitin A, we already start seeing significant reversal of this immune decline that I started to tell you about. So the inflammation is dampened. This inflammation is dampened. We see more youthful CD8T cells and a lowering of these fatigue memory cells. And then the fascinating, which I've always believed is the two roads meeting that I was saying is now these immune cells have much about 20, 30% more mitochondria and if you throw a virus on them, they kill it about 20% better. So now you have a better chance. You have given yourself this sort of rejuvenated immune system that has the resilience to fight infections or whatever.

What kind of dose of urolithin A is necessary to do this?

So this randomized clinical trial was done with a gram of urolithin A. And as a trialist, I always go with where we have the most evidence. So in our previous trials, we see the 500 milligram in a gram both impact mitochondrial health and muscle health, but the gram does impact more of the inflammation and inflammation related endpoints in the earlier trials. So we went ahead with that approach and we tested only the gram. And now we have plans to repeat the same study with the 500 milligram but a bit longer because I think it's really a kinetic of the time thing. The 500 milligram dose, you will need to intervene a bit longer.

And that's four timeline pills is one gram.

So each pill is 250 milligram and that's four timeline pills or two powders. You know, one powder has 500 milligram.

Is it better to do 500 in the morning, 500 at night, or just one gram in a single dose?

Fascinating question. And that's the randomized. I think you've asked me this before, that's a trial and I always say I need to do it, but this time I'm actually gonna do that trial. So a lot of folks, most of our trials are done with intake in the morning because just easier from a compliance perspective in a randomized trial to tell hundreds of folks to take it all in the morning. But we do think that the half life of the compound is about a day and it peaks about eight hours after you take it. So it could make sense, as you're saying, to split the dose, maybe take one 500 in the morning and then 500 in the late afternoon or early evening so that your exposure in your body, the levels are always high. And that's a trial we need to run. And next time I come back, we'll have data.

I keep hearing this over and over. I'm just kidding. So if someone's taking four either capsules or two of the powders in the morning, with or without food.

So we have done that one. So we have done the comparison where we've given a heavy breakfast meal with the powder or the pill or in a fasted state, the absorption is identical. So by that I mean you get the same levels on a fasting versus a non fasted state. And so I think the only reason we say take it in the fastest state is that potentially you may even augment some of the response because people fast overnight. And a lot of folks, I don't eat breakfast, for example. My first meal is a lunch, so I fast 18 hours. And so you're actually boosting a lot of that autophagy that is being induced by fasting. And then you take mitopure or urolitin A which I think is the foundation of which will even boost fasting or even exercise responses. That's how I approach it.

For me, it's 12:30 in the afternoon. I haven't had anything but danger coffee and a handful of supplements, including four of the timeline your lithon a capsules. But is the surface or the encapsulation material, is that enough to mess with the fast?

No, the capsules have zero calories. The powders maybe have some caloric because they're fruit flavor.

Isn't there a gelatin or something in them? I didn't look at rmhcp.

No, they're, they're, they're vegan. So they, they have a vegan shell. And the caloric value is, is, is absolutely zero. I have one of them in front.

Yeah, it can't, it can't be zero. That's like one calorie. I mean there's something in there unless it's not digestible.

So they have, so Ural 10A needs a fatty matrix. So they have MCTS. Okay.

So yeah, the MCTS alone accelerate fasting and give you more ketosis. So you've got some MCTs you've got a little bit of capsule material. Yeah. Which is probably hydroxy cellulose, which isn't actually. That's a prebiotic anyway, so it's not going to have any calories unless your gut bacteria turn it into propionic acid or something like that. Okay, so totally fasting compatible. Yeah, I do this every morning and sometimes I take a couple more at night. Do we have studies of weirdos like me who are willing to do six or eight because we're traveling or something?

Studies on. You mean fasting that.

No, not fasting, just studies of taking timeline or Urlithin A. So sometimes I'll do a gram in the morning, but then like it was a long day, I'm traveling or something. I'll do another 500 at night just because. Well, why not?

Yeah. So we've gone till a 2 gram and you get the same effects. But that. It's not like every time you double the dose, you'll get more bioavailability. I think the body needs time to absorb and clear out the excess nutrients. So having said that, 500 milligrams thrice a day, this is something, as I said, or twice a day we have to test it out.

Got it. So I love this. It's not tested, but I mean, conjecture is at the base of science, right?

Yeah. I mean, I could argue. I mean, it's a hypothesis. That's why I say research is two words. Reimagine, search. You always have an educated guess, right. In research. So you have to go back to the drawing board and you're making me think and making me go to the drawing board.

Got it. I love the elegance with which you dance away from answering that question. It's all right. Good. Scientists often say we don't really know. And I'm like, well, guess, because you know more than someone who is just flipping a coin. But I'm going to guess that. Actually, I couldn't even guess when I think about it. I mean, maybe having a big spike and then having a break, maybe arrhythmic pulsing is better than constant dosing, but I could see that being really hard to do.

Yeah. In all our studies, in the different species that were published 10 years back, I mean, you talked about 10 years of research. It's really, you know, intake every few hours. These furry rodents are taking it all the time. So after a while, and this is back to, is it always going to be inducing mitophagy? Well, you're going to clean the waste out and then the body Will allow for more healthy mitochondria to seed in. And we see that. We see PGC1 Alpha, we see more biogenesis, whether it's the immune cell or the muscle cell. So we need to figure out kind of how we pulse it and that can we induce mitophagy faster? I think it's a great idea. I'm taking quick notes.

I. I'm intrigued. You know, do like a mega dose during a fast. You take 20 grams and see what happens. And then, like, who knows what would happen? Maybe you get a big CIC effect. Who that knows? But I'm. I'm the guy who would probably try that and then either like, what happened or not like, what happened. I'm not recommending anyone do that, by the way. I'm just, like, curious. Okay, I'm going to get into skin health and, and your lithon a in a minute here. But part of the recommendations that I make for people and that you have as well is you should have a lower inflammation diet for inflamma aging. And one of the primary measures of inflammation is the omega 6 or of the inflammation in the fats from the diet is omega 6 to omega 3 ratio. So one of my companies that's part of Upgrade Labs is called Axo Health. And I just got my results back and we include an omega 6 to omega 3 ratio, and mine's at 2.6. And the longevity, people say it should be 4 to 1. That means you have four omega 6s for every omega 3 you have. But a lot of Americans are at 40 or 45 to 1, which means they're just getting crazy amounts of canola and corn. So it means you eat at restaurants, basically, or you don't know how to order at restaurants. So is there an ideal omega 6 to omega 3 ratio that you like to target? And what does urolith have to do with the inflammation levels when you're messing with your fatty acids?

So it's a good question. I don't think there is evidence of combining omega 3 with urolithin A, for example, in literature. What I can tell you is that urolithin A will increase the absorption of most nutrients we have seen. For example, we know it improves magnesium absorption. And magnesium and mitopure together are really a potent combo. Omega 3 we haven't really studied, Dave, to be honest, together, and we haven't looked the effect of urolithin A mitopure on this ratio. But something we can do, actually, in our recently completed trial that we just completed, we can easily measure because it's easy to measure this ratio. But on other markers of inflammation we have a whole panel, As I mentioned, Interleukin 6 is down. TNF Alpha is down, IL1 beta is down. These are all very potent pro inflammatory factors that are made by immune cells that will damage your gut lining, will damage your skin barrier, will probably disrupt your omega 3 to 6 ratio that you were talking about. And so chronic intake of mitopure dampens these inflammatory factors. So if you have another marker like this, sounds like it's a very innovative one. We can take a look in our clinical study.

I'm really interested in all of the things you can do to suppress inflammation without taking too many antioxidants because literature shows you make energy with oxidation. So if you take too many antioxidants, you don't get benefits from exercise. You don't, you actually suppress good things in the body. Does urolithin A have that same effect of suppressing the benefits of exercise?

No. So we've actually run a randomized clinical trial with exercise in, in conjunction in actually elite run some of them which were Olympian level middle distance runners. And what we saw in that trial that again giving mitopure with this exercise training regimen, it improved sort of their performance measures up to a certain extent. But the real dramatic effect was really blunting this exercise induced inflammation and muscle damage. So most athletes with overtraining, they get this real big spike of CRP of interleukin 6 and they have an increase increase of a muscle damage factor called creatine kinase. We see all of them blunted when given in conjunction with exercise. So that's where I see really a value in the recovery field of mitopur in with exercise.

Okay. So we don't run the risk of taking too much timeline or urolithin A with exercise because it helps exercise. But if you were to take vitamin EE or even CoQ10, which I'm a huge fan of, if you're doing that with exercise, it actually might blunt the responses of exercise.

So there are some things like as you mentioned that that are blunted that blunt these elite exercise responses in runners and cyclists. We ran this study exactly with one of the top sports researchers for that reason because a we wanted to see the absorption. A lot of nutrients are not studied. Most athletes or well trained folks absorb things differently than let's say the regular joes. And so what we see is similar levels of exposure and we see that we blunt the muscle damage and we really have an anti Inflammatory response in these folks? Well, in fact, any population, any trial I've looked, I've seen that anti inflammatory aspect of urolithin A.

Okay, that's pretty cool. I wish would, I would say that this is one of those foundational longevity and performance supplements that I, I just truly believe in. And one of the reasons is that there isn't a risk of, of taking away benefits from exercise or other beneficial stressors in the body. Which is why I'm. That was one of the many reasons that just as a longevity guy, I think this stuff is pretty cool. Let's talk about skin. So what does urolithin A do specifically for skin repair?

Yeah, so this started as a weakened idea. Not that we didn't have a lot of work already in our regular, you know, with a lot of the scientists here in timeline, we said, well this stuff gets in the body, has all these great effects. What if we actually put it in a cream and actually looked at, at what the effects are directly on skin cells. And a lot of times in the longevity field people were asking me, well, what does improving mitochondrial function mean? Should I feel more energy? What do I see on my face every morning? And so a lot of yes, you can look at energy, VO2 max and strength measures. But that led to the idea, well, what can people see on their face? Well, let's put it on a cream and see the effects. And so we started actually studying skin cells from young and old people. And I couldn't believe that the exact same hallmarks of aging were going down. So you had chronic inflammation, you had, you know, because of excessive UV damage in the skin cells, you had photo damage taking place causing inflammation. You had the mitochondria in the skin field are very poorly studied. And we started looking at young fibroblasts versus old fibroblasts. And the number feature that was down was poor mitochondrial health in these skin cells that are called fibroblasts. And so we started of course adding uretinae mitopure into and seeing if you could reverse it. And we did see the same reversal we were seeing, for example, on muscle and immune cells. And that led to a whole plethora of randomized clinical trials where we designed the topical creams. We took volunteers that were men, women with wrinkles, poor skin hydration, poor skin barrier. And these folks applied these skin creams for up to two months. And we took skin biopsies as well just to really go deep into the biology. And we saw a reversal to a certain extent of the skin wrinkles better hydration. And the real key finding was that we urolithin a mitopur topically applied stop these collagen degrading enzymes that are existing in our skin cells called matrix metalloproteinases. These are called MMP that really go up with skin aging. And that was blunted. So I, I think this is sort of a two prong approach. There's things like retinol Right. In the skin aging field that do attack wrinkles, but they are. They leave your skin sensitive and a bit irritant. And so I think this is a very natural, safe way to counteract different features of skin aging.

All right, you talked about a Super nerdy topic. NNPs. They're one of my favorite unknown longevity factors. Define mmps. Talk a little bit more about what they do in the body and outside the body and where they come from.

Yeah. So, you know, wherever there's collagen, whether in our joints or skin or, you know, collagen is. People don't realize a lot of the collagen and proteins and things also get synthesized in their mitochondria. So if you think about it, collagen, with aging levels decline, and you have all these collagen supplements that people are, are selling. But these are, these are like proteins that will get chopped into amino acids. So the holy grail in the whole aging field is to attack these set of enzymes called mmps, which stands for matric metalloproteinases. And there's several of them. These are enzymes that basically go up with aging. And so they keep chopping collagen and degrading collagen. And so the good collagen never stays around with the aging process. And that leads to, you know, loose skin that you think that comes with, you know, the saggy skin, the wrinkling of the skin. And so there are ways out there if you can attack the activity of these enzymes and prevent the degradation of cognitive.